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Drugs 2005; 65 (3): 385-411REVIEW ARTICLE 0012-6667/05/0003-0385/$39.95/0
2005 Adis Data Information BV. All rights reserved.
Oral Antidiabetic AgentsCurrent Role in Type 2 Diabetes Mellitus
Andrew J. Krentz1 and Clifford J. Bailey2
1 Southampton University Hospitals NHS Trust, Southampton, UK2 Life and Health Sciences, Aston Pharmacy School, Aston University, Birmingham, UK
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3861. Insulin Secretagogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
1.1 Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3901.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
1.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3911.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
1.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3931.1.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
1.1.6 New Formulations of Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3951.2 Rapid-Acting Prandial Insulin Releasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
1.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
1.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3961.2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
1.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3961.2.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
2. -Glucosidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3972.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3972.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3982.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
3. Insulin Sensitisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3993.1 Biguanides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
3.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3993.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4013.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
3.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4023.1.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
3.2 Thiazolidinediones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4043.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
3.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4043.2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
3.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4073.2.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
4. Summary and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
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386 Krentz & Bailey
Type 2 diabetes mellitus is a progressive and complex disorder that is difficultAbstractto treat effectively in the long term. The majority of patients are overweight or
obese at diagnosis and will be unable to achieve or sustain near normoglycaemiawithout oral antidiabetic agents; a sizeable proportion of patients will eventually
require insulin therapy to maintain long-term glycaemic control, either as mono-
therapy or in conjunction with oral antidiabetic therapy. The frequent need for
escalating therapy is held to reflect progressive loss of islet -cell function,usually in the presence of obesity-related insulin resistance.
Todays clinicians are presented with an extensive range of oral antidiabetic
drugs for type 2 diabetes. The main classes are heterogeneous in their modes of
action, safety profiles and tolerability. These main classes include agents that
stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues),
reduce hepatic glucose production (biguanides), delay digestion and absorption of
intestinal carbohydrate (-glucosidase inhibitors) or improve insulin action (thia-zolidinediones).
The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the
benefits of intensified glycaemic control on microvascular complications in newly
diagnosed patients with type 2 diabetes. However, the picture was less clearcut
with regard to macrovascular disease, with neither sulphonylureas nor insulin
significantly reducing cardiovascular events. The impact of oral antidiabetic
agents on atherosclerosis beyond expected effects on glycaemic control is an
increasingly important consideration. In the UKPDS, overweight and obese
patients randomised to initial monotherapy with metformin experienced signif-
icant reductions in myocardial infarction and diabetes-related deaths. Metformin
does not promote weight gain and has beneficial effects on several cardiovascular
risk factors. Accordingly, metformin is widely regarded as the drug of choice for
most patients with type 2 diabetes. Concern about cardiovascular safety of
sulphonylureas has largely dissipated with generally reassuring results from
clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study
showed that intensive target-driven, multifactorial approach to management,
based around a sulphonylurea, reduced the risk of both micro- and macrovascular
complications in high-risk patients. Theoretical advantages of selectively target-
ing postprandial hyperglycaemia require confirmation in clinical trials of drugs
with preferential effects on this facet of hyperglycaemia are currently in progress.
The insulin-sensitising thiazolidinedione class of antidiabetic agents has poten-tially advantageous effects on multiple components of the metabolic syndrome;
the results of clinical trials with cardiovascular endpoints are awaited.
The selection of initial monotherapy is based on a clinical and biochemical
assessment of the patient, safety considerations being paramount. In some circum-
stances, for example pregnancy or severe hepatic or renal impairment, insulin may
be the treatment of choice when nonpharmacological measures prove inadequate.
Insulin is also required for metabolic decompensation, that is, incipient or actual
diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain
comorbidities, for example presentation with myocardial infarction during other
acute intercurrent illness, may make insulin the best option.
Oral antidiabetic agents should be initiated at a low dose and titrated upaccording to glycaemic response, as judged by measurement of glycosylated
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Oral Antidiabetic Agents 387
haemoglobin (HbA1c) concentration, supplemented in some patients by self
monitoring of capillary blood glucose. The average glucose-lowering effect of the
major classes of oral antidiabetic agents is broadly similar (averaging a 12%
reduction in HbA1c), -glucosidase inhibitors being rather less effective. Tailor-ing the treatment to the individual patient is an important principle. Doses are
gradually titrated up according to response. However, the maximal glucose-lower-
ing action for sulphonylureas is usually attained at appreciably lower doses
(approximately 50%) than the manufacturers recommended daily maximum.
Combinations of certain agents, for example a secretagogue plus a biguanide or a
thiazolidinedione, are logical and widely used, and combination preparations are
now available in some countries. While the benefits of metformin added to a
sulphonylurea were initially less favourable in the UKPDS, longer-term data have
allayed concern. When considering long-term therapy, issues such as tolerability
and convenience are important additional considerations.Neither sulphonylureas nor biguanides are able to appreciably alter the rate of
progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data
suggesting that thiazolidinediones may provide better long-term glycaemic stabil-
ity are currently being tested in clinical trials; current evidence, while encourag-
ing, is not conclusive.
Delayed progression from glucose intolerance to type 2 diabetes in high-risk
individuals with glucose intolerance has been demonstrated with troglitazone,
metformin and acarbose. However, intensive lifestyle intervention can be more
effective than drug therapy, at least in the setting of interventional clinical trials.
No antidiabetic drugs are presently licensed for use in prediabetic individuals.
In 1998, the results of the randomised, multicen- management plan that encompasses effective treat-
tre UKPDS (United Kingdom Prospective Diabetes ment of hypertension and dyslipidaemia;[2-6] both
Study)[1] provided firm evidence of the importance are commonly encountered in patients with type 2of long-term glycaemic control in middle-aged pa-
tients with newly diagnosed type 2 diabetes mel-
litus. Compared with dietary manipulation alone,
intensified therapy in the form of oral antidiabetic
agents or insulin significantly reduced the develop-
ment of microvascular complications (table I).[1]
This knowledge drives current clinical practice, in
which treatment is directed to the attainment of
near-normoglycaemia, i.e. glycosylated haemo-
globin (HbA1c) concentrations of 6.57.0%.[2-4]
While such targets may be perceived as being un-
realistic for many perhaps most patients, there is
a broad consensus that chronic hyperglycaemia
should be managed as well as is possible, weighing
safety and quality-of-life considerations on an indi-
vidual basis. It is important to bear in mind thatglycaemic control is just one aspect of an overall
Table I. Summary of main results of UKPDS (United Kingdom
Prospective Diabetes Study) glycaemic control study.[1] Relative
risk (RR) reductions in clinical endpoints for patients randomised to
intensive (i.e. sulphonylurea or insulin) vs conventional therapy (i.e.
diet)
Endpoints RR for Confidence Log-rank
intensive intervala p-value
therapy
Aggregate endpointsb
Diabetes-related endpoints 0.88 0.79, 0.99 0.029
Microvascular complications 0.75 0.60, 0.93 0.0099
Single endpoints
Sudden death 0.54 0.24, 1.21 0.047
Retinal photocoagulation 0.71 0.53, 0.96 0.0031
Cataract extraction 0.76 0.53, 1.08 0.046
a 95% Confidence interval for aggregate endpoints; 99%
confidence interval for single endpoints.b As defined and ascertained in UKPDS 33.[1]
2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
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388 Krentz & Bailey
Table II. Main results for intensive (n = 80) vs conventional (n = 80) treatment of patients with type 2 diabetes mellitus and microalbuminuria.
Mean follow-up was 7.8 years[8]
Outcomes Intensive (%) Conventional (%) Adjusted HR (95% CI) RRR (95% CI) NNT (95% CI)
Composite endpoint 24 44 0.47 (0.22, 0.74) 5 (3, 19)
nephropathy 24 47 61% (13, 83) 4 (3, 14)
retinopathy 52 71 58% (14, 79) 5 (3, 35)
autonomic neuropathy 36 64 63% (21, 82) 4 (2, 9)
HR = hazard ratio; NNT = number needed to treat; RRR = relative risk reduction.
diabetes and are regarded as important modifiable physical activity. The objective is always to improve
risk factors for atherosclerosis, the principal cause metabolic control through reductions in bodyweight
of premature mortality. Thus, a combined mul- obesity being present in the majority of patients
tifactorial therapeutic approach is required to max- and other lifestyle measures that help improve insu-
imise the impact of lifestyle and drug therapy on lin sensitivity. However, it is recognised that even ifchronic micro- and macrovascular complications. diet and exercise advice is successfully implement-
Since management of chronic vascular and neuro- ed, the majority of patients will require pharmaco-
pathic complications accounts for the majority of logical therapy in the medium- to long term. Thus,
health service spending for diabetes, such an ap- only 25% of patients in UKPDS maintained a HbA1cproach is likely to be cost effective.[7] The Steno-2 level
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Oral Antidiabetic Agents 389
obese, sedentary middle-aged patients. Failure to diabetes. We consider both well established drugs
respond rapidly (i.e. within a week or two) to an oral and recent additions to the armamentarium. For each
agent in a patient thought to be complying with the class of agents we present an outline of the mode of
dietary advice usually signals the need for early use action, pharmacokinetics, indications and contrain-
of insulin. If a partial response is observed, dose dications, efficacy, safety and tolerability, current
escalation is followed by step-wise addition of com- place in management and future prospects, includ-
plementary drugs (figure 1). Insulin is usually re- ing role in prevention of type 2 diabetes. We have
served for patients: (i) who fail to respond adequate- grouped the drugs according to their principal mode
ly to a combination of oral agents; (ii) in whom of action: (i) those that increase insulin secretion
control deteriorates despite logical and adequate (insulin secretagogues); (ii) drugs delaying the rate
drug combinations; or (iii) for whom safety and of digestion and absorption of carbohydrates (-efficacy considerations favour its use as the drug of glucosidase inhibitors); and (iii) those with direct
choice, for example during pregnancy, or in patients effects on insulin-responsive tissues (insulin-sen-
with severe hepatic or renal impairment.[10] Several sitising agents). This sequence should not be taken
classes of oral antidiabetic agents are currently to imply a hierarchy in terms of efficacy or merit.
available, the range of options having enjoyed a The recognition that type 2 diabetes is usually a
welcome expansion in recent years. However, the progressive disease implies that drug dosages will
evidence base and clinical experience vary consider- need to be increased or therapy moved to another
ably not only between classes but also between stage in the treatment algorithm.[2,4]
drugs drawn from the same class. As a result, pre-While this article primarily reflects current prac-
scribing decisions often appear to be made on rathertice in the UK, we have endeavoured to provide a
subjective grounds, such as familiarity with a partic-review that acknowledges important differences in
ular drug; this practice may help to explain notable
prescribing in other countries. A word about moni-regional differences in prescribing. toring: assessing the response to antidiabetic therapy
In the remainder of this article we focus on involves periodic generally 3- to 6-monthly
treatment of hyperglycaemia in patients with type 2 measurement of HbA1c. This approach, which is
Aim
Relieve symptoms,improve glycaemic
control, enhance
quality of life
Diagnosis
Diet, exercise, weight control
and health education
Oral agent monotherapy:metformin, sulphonylurea, meglitinide,
thiazolidinedione1, acarbose
Oral agent combination therapy
(using two different classes)
Insulin or insulin plus an oral agent
Procedure
Move to next stageif there is inadequate
control of glycaemia
or inadequate relief
of symptoms
Fig. 1. An algorithm for the treatment of type 2 diabetes mellitus. The progressive hyperglycaemia in type 2 diabetes requires a stepped-
care approach with treatment being modified and added over time. Rapid progression to the next stage is recommended if the glycaemic
target is not achieved. Late introduction of combinations of oral antidiabetic agents is often a prelude to insulin treatment. 1 Note that in
Europe, thiazolidinediones and nateglinide have limited licenses. The -glucosidase inhibitor miglitol is also available in some countries(reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press).
2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
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390 Krentz & Bailey
recommended in the UK, can be usefully comple- nylureas with respect to the risks of weight gain and
mented by self measurement of capillary blood glu- hypoglycaemia. Compared with older sulpho-
cose in selected, empowered patients and in particu- nylureas, glimepiride is relatively expensive and
lar clinical scenarios, for example in patients in clinical outcome data are not available, as they are
whom iatrogenic hypoglycaemia is a concern. for the agents used in the UKPDS. The clinical
relevance of theoretical, but much debated, effects
of glimepiride on ischaemic preconditioning 1. Insulin Secretagogueswhereby a brief episode of ischaemia protects the
myocardium against the detrimental effects of sub-1.1 Sulphonylureas sequent and more severe interruption of perfusion
remain uncertain. The issues of the importance ofSulphonylureas have been extensively used for ischaemic preconditioning and the possible influ-
the treatment of type 2 diabetes for nearly 50 years. ence of different sulphonylureas continue to be de-
They lower blood glucose concentrations primarily bated (see section 1.1.5).[14]
by stimulating insulin secretion from the cells ofthe pancreatic islets. By the 1960s several sulpho-
1.1.1 Mode of Actionnylureas were available, including tolbutamide,
Sulphonylureas have direct effects on the insulin-acetohexamide, tolazamide and chlorpropamide, of-producing islet cells. The drugs bind to the -cellfering a range of pharmacokinetic options. How-sulphonylurea receptor (SUR)-1, part of a trans-ever, doubts about safety were raised in the 1970s. A
membrane complex with adenosine 5-triphosphate-large US multicentre trial of antidiabetic therapy,sensitive Kir 6.2 potassium channels (KATP chan-the UGDP (University Group Diabetes Program)[11]
nels).[14,15] Binding of the sulphonylurea closes thesereported apparent detrimental cardiovascular effects
KATP channels; this reduces cellular potassium ef-of tolbutamide. The UGDP was heavily criticisedfor perceived methodological failings and its find- flux favouring membrane depolarisation. In turn,
ings were far from being universally accepted. Sub- depolarisation opens voltage-dependent calcium
sequent observational and randomised clinical stud- channels, resulting in an influx of calcium that acti-
ies using sulphonylureas have provided mixed evi- vates calcium-dependent proteins that control the
dence, but a review of the available literature release of insulin (figure 2). When sulphonylureas
provides little in the way of convincing evidence of interact with SUR1 in the -cell plasma membranecardiovascular toxicity.[12] Indeed, some studies they cause prompt release of pre-formed insulin
have reported a decreased incidence of cardio- granules adjacent to the plasma membrane the so-
vascular events in subjects with lesser degrees of called first phase of insulin release.[16] Sulpho-
glucose intolerance who received sulphony- nylureas also increase the extended (second phase)
lureas.[12] The UKPDS investigators did not find any of insulin release that begins approximately 10 min-
increase in risk of myocardial infarction among pa- utes later as insulin granules are translocated to the
tients treated with sulphonylureas compared with membrane from within the cell.[17] The protractedpatients randomised to insulin as monotherapy.[1] stimulation of the second phase of insulin release
The Steno-2 Study,[8] has already been mentioned. involves the secretion of newly formed insulin gran-
ules. The increased release of insulin continuesA succession of more potent so-called second-
while there is ongoing drug stimulation, providedgeneration sulphonylureas emerged in the 1970s and
the cells are fully functional. Sulphonylureas can1980s, for example glibenclamide (glyburide),cause hypoglycaemia since insulin release is initiat-gliclazide and glipizide. The latest, glimepiride, was
ed even when glucose concentrations are below theintroduced in the late 1990s.[13] Glimepiride is a
normal threshold for glucose-stimulated insulin re-once-daily drug for which claims have been madelease (approximately 5 mmol/L).that it might offer advantages over other sulpho-
2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
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Oral Antidiabetic Agents 391
Glucokinase
GLUT2
Glucose
Glucose
metabolism
Insulin
Exocytosis
ATP
Insulin
Recepto
rs
Adrene
rgic
receptor
s
Ca2+
channel
Depolarisa
tion
SUR1
Kir6.2
KATP
channe
l
cAMP
PDE
inhibitors
GLP-1
Exenatide
2-adrenoceptorantagonists
PKA
Proinsulin
biosynthesis
Succinate esters
Ca2+-sensitive
proteins
SulphonylureasRepaglinide
Nateglinide
Fig. 2. The insulin-releasing effect of sulphonylureas and other agents on the pancreatic islet cell. Sulphonylureas bind to the sulphonylu-rea receptor (SUR)-1 located within the plasma membrane. This closes Kir 6.2 potassium channels which reduces potassium efflux,
depolarises the cell and opens voltage-dependent calcium influx channels. Raised intracellular calcium brings about insulin release.
According to the stimulus-secretion model, metabolism of glucose generates adenosine 5-triphosphate (ATP) leading to closure ofpotassium channels, permitting the normal cell to link insulin secretion closely to glucose concentration. Sulphonylureas may alsoenhance nutrient-stimulated insulin secretion by other actions on the cell. Other secretagogues, e.g. repaglinide, nateglinide, alsostimulate insulin secretion via the SUR-Kir 6.2 complex. Other agents, e.g. phosphodiesterase (PDE) inhibitors, glucagon-like peptide
(GLP)-1 (736 amide), act via cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) to promote proinsulin synthesis
(reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press). GLUT2 = glucose transporter-2.
1.1.2 Pharmacokinetics liver, although metabolites and their routes of elimi-
nation vary considerably between compounds.The principal distinguishing feature between dif-
Since all sulphonylureas are highly bound to plasmaferent sulphonylureas relates to their pharmacokine-proteins they have the potential to interact with othertic characteristics (table III). Duration of action var-drugs sharing this binding, for example salicylates,ies from 24 hours forsulphonamides and warfarin; displacement from cir-chlorpropamide because of differences in (i) rates ofculating proteins has been implicated in cases ofmetabolism; (ii) activity of metabolites; and (iii)severe sulphonylurea-induced hypoglycaemia (tablerates of elimination.[18] These properties have im-IV).portant implications for the risk of hypoglycaemia
associated with various sulphonylureas, an issue that 1.1.3 Indications and Contraindications
is further complicated by retarded release prepara- Sulphonylureas remain a popular choice as first-tions of some compounds. All sulphonylureas are line oral therapy for patients with type 2 diabetes
well absorbed and most reach peak plasma concen- who have not achieved or maintained adequate gly-tration in 24 hours. They are metabolised in the caemic control using nonpharmacological measures.
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392 Krentz & Bailey
Table III. Pharmacokinetic properties of sulphonylureas[19]
Sulphonylureas Daily dosage (mg) Duration of actiona Activity of metabolites Main route of
elimination
First generationChlorpropamideb 100500 Long Active Urine >90%
Tolbutamidec 5002000 Short Inactive Urine 100%
Second generation
Glibenclamide (glyburide) 2.515 Intermediate to long Active Bile 50%
Glimepiride 16 Intermediate Active Urine 80%
Glipizide 2.520 Short to intermediate Inactive Urine 70%
Gliquidone 15180 Short to intermediate Inactive Bile 95%
Gliclazide 40320d Intermediate Inactive Urine 65%
a Long >24h; intermediate 1224h; short
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Oral Antidiabetic Agents 393
be monitored by periodic measurement of HbA1c (or nylurea therapy generally has modest effects on
fructosamine if HbA1c is not available). blood lipid profiles, although some studies have
noted a small decrease in plasma triglyceride levels1.1.4 Efficacy possibly linked to improved glycaemic control
The blood glucose-lowering efficacy of sulpho- and minor increments in high-density lipoprotein
nylureas has been evaluated in many retrospective (HDL)-cholesterol. When a sulphonylurea is used in
and prospective studies, and from decades of collec- combination with another antidiabetic agent, the
tive worldwide clinical experience. When used as glucose-lowering efficacy of the sulphonylurea is
monotherapy in patients inadequately controlled by approximately additive to the effect of the other
nonpharmacological measures, sulphonylureas can agent. Once again, response is crucially dependent
be expected to reduce fasting plasma glucose by an on the presence of adequate -cell function. Earlyaverage of 24 mmol/L accompanied by a decrease use of such combination therapy is indicated when
in HbA1c of 12%.[4,19,21] However, individual re- optimal titration of a single agent does not achieve
sponses are variable. Since the hypoglycaemic ef- adequate glycaemic control.fect of sulphonylureas is attributable to increased The combination of two different types of agentsinsulin secretion, the effectiveness of these drugs is is more likely to achieve glycaemic targets, albeitdependent on adequate -cell function. The afore- for a variable period of time. If combination therapymentioned progressive -cell failure that determines is started at a stage when hyperglycaemia is alreadythe natural history of type 2 diabetes may require an marked (after failure of monotherapy), then -cellincreased dosage of sulphonylureas if glycaemic depletion is likely to be advanced. Under thesecontrol deteriorates. Rapid and uncontrollable dete- circumstances, oral combination therapy is likely torioration of glycaemic control during sulphonylurea offer limited benefit and the need for an early movetherapy is sometimes termed secondary sulphony- to insulin treatment is usually clear. Since there are
lurea failure. This phenomenon, which is some- occasional exceptions to this rule, a limited trial ofthing of a misnomer, occurs in approximately combination oral therapy may be worthwhile. How-510% of patients per annum with suggestions of ever, the temptation to procrastinate unduly ondifferences in failure rates between some com- transferring the patient to insulin treatment shouldpounds.[21,22] The inability to maintain acceptable be firmly resisted, not least since some patientsglycaemic control is common to all sulphonylureas derive rapid symptomatic benefit from insulin ther-and is held to reflect an advanced stage of -cell apy. Impending metabolic decompensation, with orfailure, that is, it is a reflection of disease progres- without ketosis, mandates immediate insulin treat-sion rather than a true failure of therapy. Individuals ment; more severe degrees of decompensation, forwho have greater degrees of-cell reserve usually example obtundation, dehydration, ketosis-asso-respond well to sulphonylureas; early use of sulpho- ciated vomiting, necessitates emergency hospitalisa-nylureas as first-line monotherapy in these patients tion for treatment with intravenous insulin, fluidswill produce better blood glucose lowering than late and electrolytes.intervention in patients with severely compromised
-cell function. 1.1.5 Adverse EventsThe plasma insulin concentrations achieved Hypoglycaemia, usually subclinical or minor but
during sulphonylurea therapy do not usually extend occasionally life threatening, is the most common
beyond the range observed in the general non-diabe- and potentially most serious adverse effect of sul-
tic population (including those with impaired glu- phonylurea therapy.[23] Patients receiving sulpho-
cose tolerance), and suggestions that sulphonylurea- nylureas should receive instruction on the recogni-
induced hyperinsulinaemia might increase the risk tion and prevention of hypoglycaemia and the
of detrimental insulin-induced effects on the cardio- prompt actions they must take should warningvascular system remain unsubstantiated.[12] Sulpho- symptoms develop. Severe protracted hypogly-
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394 Krentz & Bailey
caemia is more likely with longer-acting sulpho- patients receiving insulin therapy is orders of magni-
nylureas such as glibenclamide, with tolbutamide tude higher. However, this does not detract from the
holding the lowest place in the hierarchy of risk (see importance of sulphonylurea-induced hypogly-
also section 1.1.6). Individuals with irregular eating caemia. Minor recurrent hypoglycaemia should
habits (see section 1.2.3) or excessive alcohol con- prompt a reassessment of the choice of agent andsumption are at higher risk of sulphonylurea-in- consideration of an alternative secretagogue, for ex-duced hypoglycaemia. As mentioned in section ample a rapid-acting insulin releaser (see section1.1.3, hypoglycaemia is also more likely to occur in 1.2). The treatment schedule, the possibility of drugpatients with satisfactory glycaemic control, as indi- interactions (table IV) and relevant features of thecated by an HbA1c concentration within, or just patients lifestyle, such as diet, meal patterns andabove, the non-diabetic reference range. These pa- alcohol use, should be reviewed. Severe episodes oftients should always be questioned directly about sulphonylurea-induced hypoglycaemia mandate im-recent symptoms of hypoglycaemia, although their mediate admission to hospital: treatment with a con-nonspecific nature can raise problems of over-diag- tinuous intravenous infusion of dextrose may benosis; self-monitoring of capillary blood glucose required for several days. There is a tendency forconcentrations during suggestive episodes should hypoglycaemia to recur shortly after initial resusci-help to clarify this issue, although uncertainties may tation with intravenous dextrose; the patient shouldnot be completely dispelled. If there is continuing not be prematurely discharged after emergencydoubt, a temporary reduction in dose is usually treatment. Where accumulation of chlorpropamideindicated. Estimates of the incidence of mild hypo- is suspected, renal elimination may be enhanced byglycaemia, that is, not requiring assistance from forced alkaline diuresis. The vasodilator diazoxideanother individual, are often based on symptoms and the somatostatin analogue octreotide[24] havewhich have not necessarily been confirmed by con- been used successfully to reversibly inhibit insulin
temporaneous self-measurement of capillary blood secretion in severe sulphonylurea-induced hypogly-glucose. In the UKPDS, for example, about 20% of
caemia, thereby reducing intravenous dextrose re-sulphonylurea-treated patients reported one or more
quirements. These drugs should be regarded as po-episodes suggestive of hypoglycaemia annually;
tentially useful adjuncts to intravenous glucose inother studies have suggested similar rates.[23] The
some patients; octreotide avoids the adverse haemo-timing of hypoglycaemia tends to reflect the
dynamic effects of diazoxide, an obsolete antihyper-pharmacokinetics of the sulphonylurea. Thus, gli-
tensive agent that may pose a hazard in the elderlybenclamide has a propensity to cause inter-prandial
patient with compromised cardiovascular reflexes.hypoglycaemia whereas chlorpropamide tends to
Other adverse events of sulphonylureas includeinduce hypoglycaemia in the pre-breakfast period.uncommon sensitivity reactions usually cutaneousMore severe hypoglycaemia (i.e. requiring assis- that are usually transient; erythema multiforme istance) occurred in about 1% of sulphonylurea-treat-rare. Fever, jaundice and blood dyscrasias are veryed patients annually in the UKPDS. In general,rare; some sulphonylureas can reportedly precipitatelower rates (approximately 0.22.5 episodes peracute porphyria in predisposed individuals. In its1000 patient-years) have been reported from ad-heyday, chlorpropamide was notorious for causingverse event reporting to regulatory authorities orunpleasant facial flushing after consuming smallfrom physician-completed questionnaires. The mor-quantities of alcohol; photosensitivity has also beentality risk from severe sulphonylurea-induced hypo-reported. Chlorpropamide could also increase renalglycaemia has been calculated to be 0.0140.033 per
sensitivity to antidiuretic hormone, occasionally1000 patient-years.[23] Predictably, longer-acting
causing water retention with hyponatraemia. In con-high-potency agents, such as glibenclamide, appear
trast, glibenclamide is credited with a mild diureticto carry the greater mortality risk. For comparison,action. Weight gain is regarded as a class effect ofthe occurrence of severe hypoglycaemia induced in
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Oral Antidiabetic Agents 395
sulphonylurea therapy, typically amounting to held to be equivalent to 80mg of unmodified glicla-
14kg and stabilising after about 6 months. This zide. In a recent 6-month comparative multicentre
weight gain, which is always unwelcome, is thought study, gliclazide MR was associated with approxi-
to reflect the anabolic effects of increased plasma mately 50% reduction in episodes of minor hypogly-
insulin concentrations; some studies have suggested caemia compared with glimepiride, at similar levels
that reduced loss of calories as glucose in the urine of glycaemic control; no episodes of severe hypo-
may account for the majority of the weight glycaemia were observed with either agent in this
gain.[19,21] study.[26]
The saga of the questionable cardiovascular safe-1.2 Rapid-Acting Prandial Insulin Releasersty of the sulphonylureas was given a nudge by the
discovery that cardiac muscle and vascular smoothUnder experimental conditions the first phase of
muscle express isoforms of the SUR2A and SUR2B.glucose-stimulated insulin secretion is diminished
Sulphonylureas that contain a benzamido group (gli-
early in the natural history of type 2 diabetes. Thebenclamide, glipizide, glimepiride) can bind to prompt physiological rise in plasma insulin in res-SUR2A and SUR2B,[15] whereas those without (e.g.
ponse to meals is attenuated and its peak delayed.tolbutamide, chlorpropamide and gliclazide) show
An initial surge of insulin release appears to bevery little interaction with the cardiac and vascular
particularly important for effective postprandialSUR receptors. The effects of the KATP channel suppression of hepatic glucose production; failure toopener nicorandil (an anti-anginal drug with cardi-
suppress endogenous glucose production exacer-oprotective properties) are blocked by sulpho-
bates postprandial hyperglycaemia. Because post-nylureas that have a benzamido group.[15] The clin-
prandial hyperglycaemia contributes to elevatedical implications of these observations remain to be
HbA1c levels it is a logical therapeutic target. Rapid-determined. Although very high concentrations of
acting prandial insulin releasers are available that
sulphonylureas can cause contraction of cardiac and stimulate rapid, but short-lived, insulin secre-vascular muscle, this is regarded as being unlikely to
tion.[27,28] These agents are taken orally immediatelybe clinically significant effect at therapeutic drug
before a meal. Derivatives of meglitinide, such asconcentrations. Nonetheless, on the basis of adverse
repaglinide and the phenylalanine derivative nateg-clinical experiences in high-risk patients, some high
linide, are promoted as prandial glucose regula-profile authorities continue to advocate that sulpho-
tors; in fact, fasting hyperglycaemia is also im-nylurea use be kept to a minimum in patients with
proved to a lesser extent, particularly with repagli-overt coronary artery disease.[25]
nide. Clinical experience with these agents remains
limited in most countries; these drugs are appreci-1.1.6 New Formulations of Sulphonylureas
ably more expensive than most sulphonylureas, theAlterations to the formulation of some sulpho-
latter also having the reassurance of outcome datanylureas have been undertaken to modify the dura-from the UKPDS.
tion of action.[4] For example, a micronised formula-
1.2.1 Mode of Actiontion of glibenclamide is available in the US that
increases the rate of gastrointestinal absorption, Benzamido prandial insulin releasers bind to the
thereby enabling an earlier onset of action. A longer- SUR1 in the plasma membrane of the cell at a siteacting (extended release) formulation of glipizide distinct from the sulphonylurea binding site (figure
has also been introduced. A new (modified release 2). Since the KATP channel is closed when either the
[MR]) formulation of gliclazide was launched in benzamido binding site or the sulphonylurea bind-
some countries in 2002. This formulation has been ing site on the SUR1 is bound with its respective
designed to produce an initially rapid, followed by agonist, there is no advantage in giving a prandial
steady release of the drug to enable once-daily dos- insulin releaser in addition to a sulphonylurea. How-age. For the MR formulation of gliclazide, 30mg is ever, drugs are also in development that promote -
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396 Krentz & Bailey
cell proinsulin synthesis and act via signalling path- daily dosages is a potential disincentive. Repagli-
ways distinct from the KATP channel (figure 2). The nide should ideally be taken about 1530 minutes
short half-life of repaglinide results in enhancement before a meal. Starting with a low dose, for example
of the first-phase and early second-phase of insulin 0.5mg before each main meal, the effect on gly-
secretion that is less sustained than that observed caemic control is monitored and the dosage titrated
with sulphonylureas.[27-29] Theoretical benefits on up every 2 weeks to a maximum of 4mg before each
cardiovascular outcomes from preferentially target- main meal; if a meal is not consumed the corre-
ing the postprandial period remain to be con- sponding dose of repaglinide should be omitted. If
firmed.[28,29] It is unclear whether postprandial glycaemic targets are not met, consider early intro-
hyperglycaemiaper se is detrimental to the vascular duction of combination therapy (e.g. with metfor-
endothelium or whether closely associated metabol- min). Unlike some sulphonylureas and metformin,
ic disturbances, for example dyslipidaemia, are re- repaglinide is suitable for patients with moderate
sponsible. Thus, the mechanism of the association renal impairment, although careful upward dose
between post-challenge hyperglycaemia and mor- titration and close monitoring is still recommended.tality observed in the multicentre DECODE (Diabe- In contrast with the US, the UK license for nategli-
tes Epidemiology: Collaborative analysis Of Diag- nide currently restricts use to combination therapy
nostic criteria in Europe) study is uncertain.[30] Ran- with metformin in patients who do not achieve gly-
domised trials that are currently in progress should caemic targets with the latter drug as monother-
help clarify this issue. apy.[29] In the US, nateglinide may also be used as
monotherapy or combined with a thiazolidinedione.1.2.2 Pharmacokinetics
Nateglinide should be used with caution in patientsRepaglinide is rapidly and almost completely
with hepatic disease.absorbed after oral administration, with peak plasma
concentrations achieved in about 1 hour.[27] The1.2.4 Efficacydrug is rapidly metabolised in the liver to inactiveRepaglinide (0.54mg taken about 1530 min-
metabolites, which are mainly excreted in bile.utes before meals) results in dose-dependent in-
When taken about 15 minutes before a meal, repag-creases in insulin secretion with reduced postprandi-
linide produces a prompt insulin-releasing effect,al hyperglycaemia; a lesser reduction in fasting
which is limited to a period of about 3 hours, rough-hyperglycaemia is also observed. Overall reductions
ly coinciding with the duration of meal digestion.in HbA1c are similar in magnitude to those observed
Nateglinide has a slightly faster onset and shorterwith sulphonylureas, that is 12%. Combined with
duration of action, its binding to target receptorsmetformin, nateglinide reduces HbA1c by up to
lasting only seconds. A 60mg dose of nateglinide1.5%.[28,29]
taken 20 minutes before an intravenous glucose
tolerance test restored first-phase insulin release and 1.2.5 Adverse Eventslowered glucose concentrations.[28,29]
The overall incidence of hypoglycaemic episodes
1.2.3 Indications and Contraindications is lower with repaglinide than with sulphonyureas.
Repaglinide may be used as monotherapy in pa- Sensitivity reactions, usually transient, can occur.
tients inadequately controlled by nonpharmacologi- Increased plasma levels of repaglinide have been
cal measures. Suitable candidates for rapid-acting reported when co-administered with gemfibrozil. A
insulin releasers include individuals with irregular small increase in bodyweight can be expected in
lifestyles wherein meals are unpredictable or patients starting repaglinide as initial monotherapy,
missed. The lower risk of hypoglycaemia associated but there may be little change in weight among
with its use makes repaglinide an attractive option patients switched from a sulphonylurea. Nateglinide
for some elderly patients, particularly if other agents appears to have little effect on bodyweight whenare contraindicated. However, the need for multiple combined with metformin.[29]
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Oral Antidiabetic Agents 397
Intestinal
lumen
Brush
border
Starch
Maltose
maltotriosedextrins
Sucrose
Microvillus
-Glucosidaseenzymes
-Amylase
Enterocyte
Villus
-Glucosidaseinhibitor (acarbose,miglitol, voglibose)
Fig. 3. -Glucosidase inhibitors (e.g. acarbose) competitively inhibit the activity of -glucosidase enzymes in the brush border of smallintestinal enterocytes (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press).
2. -Glucosidase Inhibitors carbohydrate digestion until further along the intes-tinal tract, in turn causing glucose absorption to be
Inhibitors of intestinal -glucosidase enzymes delayed. The -glucosidase inhibitors should be tak-retard the rate of carbohydrate digestion, thereby
en with meals containing digestible carbohydrates,providing an alternative means to reduce postpran-
not monosaccharides; these drugs generally do notdial hyperglycaemia.[31] Acarbose, the first -
significantly affect the absorption of glucose. Sinceglucosidase inhibitor to be marketed, was intro- -glucosidase inhibitors move glucose absorptionduced in the early 1990s. Recently, two additional
more distally along the intestinal tract they alteragents, miglitol and voglibose, have been intro-
glucose-dependent release of intestinal hormonesduced in some countries.[4] The -glucosidase inhib-
that enhance nutrient-induced insulin secretion. Re-itors do not cause weight gain, can reduce postpran-
lease of gastric inhibitory polypeptide, which occursdial hyperinsulinaemia and have lowered plasmamainly from the jejunal mucosa, may be reduced bytriglyceride concentrations in some studies.[31] Their-glucosidase inhibitors, whereas glucagon-likegood safety record is a further advantage, but limitedpeptide-1 (736 amide) secretion (mostly from thegastrointestinal tolerability has substantially limitedileal mucosa) is increased. Overall, -glucosidasetheir use. The relatively high cost of-glucosidase
inhibitors reduce postprandial insulin concentrationsinhibitors is another consideration that has influ- through the attenuated rise in postprandial glucoseenced prescribing. In the UK, acarbose use remainslevels.[31]low.
2.1 Mode of Action 2.2 Pharmacokinetics
The -glucosidase inhibitors competitively in-Acarbose is absorbed only to a trivial degreehibit the activity of-glucosidase enzymes in the
(
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398 Krentz & Bailey
2.3 Indications and Contraindications breast-feeding are traditionally regarded to be con-
traindications for all oral antidiabetic drugs, mainly
An -glucosidase inhibitor may be used as because of a lack of safety data rather than evidencemonotherapy for patients with type 2 diabetes that is of detrimental effects.
inadequately controlled by nonpharmacological2.4 Efficacymeasures. Because -glucosidase inhibitors target
postprandial hyperglycaemia, they can be a usefulAn -glucosidase inhibitor can reduce peak con-
first-line treatment in patients who have a combina-centrations of blood glucose and reduce interprandi-
tion of only slightly raised basal glucose concentra-al troughs. Used as monotherapy to patients who
tions and more marked postprandial hypergly-comply appropriately with dietary advice, an -
caemia. A recent multicentre clinical trial (STOP-glucosidase inhibitor will typically reduce postpran-
NIDDM [Study TO Prevent NonInsulin-Dependentdial glucose concentrations by 14 mmol/L. The
Diabetes Mellitus]) confirmed the utility of acarbose
incremental area under the postprandial plasma glu-in preventing the transition from impaired glucose cose curve can be more than halved in some individ-tolerance to diabetes[32] (see section 2.4). Acarbose
uals. There seems to be a carry-over effect thatcan be used in combination with other antidiabetic
may produce a reduction in basal glycaemia up toagents. When starting therapy with an -glucosidase
1 mmol/L. The decrease in HbA1c is usually aboutinhibitor it is said to be important to ensure that the
0.51.0%, provided that a high dose of the drug ispatient is taking a diet rich in complex carbohy-
tolerated and dietary compliance is maintained.[33]drates, as opposed to simple sugars. Acarbose
There may be a trivial alteration in the gastrointesti-should be taken with meals, starting with a low dose,
nal absorption of other oral antidiabetic agents whenfor example 50 mg/day, and slowly titrating up over
used in combination therapy. In general, the extraseveral weeks. Monitoring of glycaemic control,
benefit to glycaemic control achieved by addition of
particularly postprandially, may be helpful. The an -glucosidase inhibitor to another antidiabeticpostprandial action of these agents would not beagent is additive. In the recently published multicen-
expected to induce hypoglycaemia, at least whentre STOP-NIDDM trial acarbose reduced the risk of
they are used as monotherapy. The maximum dos-progression from impaired glucose tolerance to type
age of-glucosidase inhibitors may be limited by2 diabetes (relative hazard 0.75; 95% CI 0.63, 0.90;
gastrointestinal symptoms; this is certainly our ex-p = 0.0015).[32] This study randomised 1429 patients
perience with acarbose (see section 2.5). Intuitively,with impaired glucose tolerance to acarbose 100mg
patients experiencing gastrointestinal adverse ef-three times daily or placebo, of whom data were
fects with metformin may not be the best candidatesavailable for a modified intention-to-treat analysis
in whom to add an -glucosidase inhibitor. A his-in 1368 patients. Glucose tolerance was determined
tory of chronic intestinal disease serves as a large-using a 75g oral glucose tolerance test. Intriguingly,ly theoretical contraindication to acarbose andnew cases of hypertension and major cardiac events,
other agents in this class. High dosages of acarboseincluding overt and clinically silent myocardial in-
can occasionally increase liver enzyme concentra-farction, were also reduced by acarbose therapy.[34]
tions, and it is recommended that transaminase con-The latter were not primary endpoints of the study, a
centrations are measured at intervals in patients re-limitation acknowledged by the investigators.[34]
ceiving the maximum dosage (200mg three timesThe results of ongoing trials using acarbose and
daily in the UK, a dosage rarely attained in practiceother agents in this class are awaited.[35]
for the aforementioned reasons). If liver enzymes
are raised, the dosage of acarbose should be reduced 2.5 Adverse Effectsto a level at which normal enzyme concentrations
are re-established. Alternative causes of hepatic dys- The most common problems with -glucosidasefunction should be considered. Pregnancy and inhibitors are gastrointestinal adverse effects. In the
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Oral Antidiabetic Agents 399
STOP-NIDDM trial 31% of acarbose-treated pa- guanidine derivatives in the 1920s. These early
tients compared with 19% on placebo discontinued antidiabetic agents were all but forgotten as insulin
treatment early.[32] If the dosage is too high (relative became widely available and it was not until the late
to the amount of complex carbohydrate in the meal), 1950s that three antidiabetic biguanides were report-
undigested oligosaccharides pass into the large bow- ed: metformin, phenformin and buformin. Phen-
el.[23] Carbohydrates fermented by the flora of the formin was withdrawn in many countries in the
large bowel cause flatulence, abdominal discomfort 1970s because of a high incidence of lactic acidosis;
and sometimes diarrhoea. This is most likely to buformin received limited use in a few countries,
occur during the initial titration of the drug and can leaving metformin as the main biguanide on a global
sometimes be minimised by slow titration and by basis. Metformin is the only biguanide available in
ensuring dietary compliance with meals rich in com- the UK and, since 1995, the US.[23,40] Extensive
plex carbohydrate. In some patients the gastrointes- clinical experience with metformin has been com-
tinal symptoms may gradually subside with time, plemented by favourable results from the UKPDS.
suggesting an adaptive response within the gastroin- Metformin also enjoys the accolade of being amongtestinal tract. Hypoglycaemia is only likely to be the least expensive of the oral antidiabetic agents.
encountered when an -glucosidase inhibitor is used3.1.1 Mode of Actionin combination with a sulphonylurea or insulin.[23]
Metformin has a variety of metabolic effects,No clinically significant drug interations have beensome of which may confer clinical benefits thatreported. However, agents affecting gut motility canextend beyond glucose lowering (table V). How-potentially influence the efficacy and gastrointesti-ever, the molecular mechanisms of metformin havenal effects of acarbose; cholestyramine may in-yet to be fully identified. At the cellular level, met-crease the glucose-lowering effect of acarbose.formin improves insulin sensitivity to some extent,
an action mediated via post-receptor signalling path-3. Insulin Sensitisers ways for insulin.[41,42] Recent data have suggestedInsulin resistance is a prominent metabolic defect that adenosine 5-monophosphate-activated protein
in most patients with type 2 diabetes.[36,37] Defective
insulin action is not confined to glucose metabolism,
subtle defects also being demonstrable in the regula-
tion of other aspects of intermediary metabolism
(e.g. lipolysis), using appropriate investigative tech-
niques. Many cross-sectional and prospective stud-
ies have implicated insulin resistance in the patho-
genesis of type 2 diabetes and the related metabolic
syndrome of cardiovascular risk.[38] Therefore, de-fective insulin action at target tissue level is an
attractive therapeutic target in type 2 diabetes.[39]
The biguanides and, in particular, the thiazolidinedi-
ones act directly against insulin resistance, and so
are regarded as insulin sensitising drugs.
3.1 Biguanides
The finding that Galega officinalis (goats rue or
French lilac), historically used as a traditional treat-
ment for diabetes in Europe, was rich in guanidineled to the introduction of several glucose-lowering
Table V. Metabolic and vascular effects of metformin
Anti-hyperglycaemic action
suppresses hepatic glucose output
increases insulin-mediated glucose utilisation
decreases fatty acid oxidation
increases splanchnic glucose turnover
Weight stabilisation or reduction
Improves lipid profilereduces hypertriglyceridaemia
lowers plasma fatty acids and LDL-cholesterol; raises HDL-
cholesterol in some patients
No risk of serious hypoglycaemia
Counters insulin resistance
decreases endogenous or exogenous insulin requirements
reduces basal plasma insulin concentrations
Vascular effects
increased fibrinolysis
decreases PAI-1 levels
improved endothelial function
HDL = high-density lipoprotein; LDL = low-density lipoprotein;PAI-1 = plasminogen activator inhibitor-1.
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400 Krentz & Bailey
Metformin
Anaerobic glucosemetabolism
Glucose uptakeand oxidation
Glucoseuptake and
oxidation
Glycogenesis
Oxidationof FA
Fatty acids
Intestine Fat
Glyconeogenesis
Glycogenesis
Oxidation of FA
Liver Muscle
Lactate
Hepatic glucoseproduction
Insulin-mediatedglucose disposal
Blood glucoseconcentration
Fig. 4. Actions of metformin. Inhibition of hepatic glucose production is regarded as the principal mechanism through which metformin
lowers blood glucose (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press). FA = fatty acids;
indicates increase; indicates decrease.
kinase (AMPK) is a possible intracellular target of nant glucose-lowering mechanism of action of met-
metformin.[43] Through phosphorylation of key pro- formin is to reduce excessive rates of hepatic glu-teins, AMPK acts as a regulator of glucose and lipid cose production. Metformin reduces gluconeogene-
metabolism and cellular energy regulation.[44] Since sis by increasing hepatic sensitivity to insulin (figure
metformin lowers blood glucose concentrations 4) and decreasing the hepatic extraction of certain
without causing overt hypoglycaemia it is most ap- gluconeogenic substrates (e.g. lactate). Hepatic
propriately classed as an anti-hyperglycaemic as glycogenolysis is also decreased by metformin. In-
distinct from hypoglycaemic agent. The clinical sulin-stimulated glucose uptake in skeletal muscle is
efficacy of metformin in patients with type 2 diabe- enhanced by metformin. This involves an increase
tes requires the presence of insulin. The drug does in the movement of insulin-sensitive glucose trans-
not stimulate insulin release and a small decrease in porter molecules to the cell membrane; an increase
fasting insulin concentrations is typically observed in the activity of the enzyme glycogen synthasein patients with hyperinsulinaemia.[21] The predomi- promotes synthesis of glycogen. Metformin also
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Oral Antidiabetic Agents 401
acts in an insulin-independent manner to suppress other class of oral antidiabetic agent or with insulin.
oxidation of fatty acids and to reduce triglyceride The drug is contraindicated in patients with im-levels in patients with hypertriglyceridaemia.[19]
paired renal function (i.e. serum creatinineThis reduces the energy supply for hepatic gluco- >120130 mol/L, depending on lean body mass),neogenesis and has favourable effects on the glu- as a precaution against drug accumulation. Cardiaccose-fatty acid (Randle) cycle (in which fatty acids or respiratory insufficiency, or any other conditionare held to compete with glucose as a cellular energy
predisposing to hypoxia or reduced perfusion (e.g.source).[37] Glucose metabolism in the splanchnic
hypotension, septicaemia) are further contraindica-bed is increased by metformin through insulin-inde-
tions, as well as liver disease, alcohol abuse and apendent mechanisms. This may contribute to the
history of metabolic acidosis. Metformin can beblood glucose-lowering effect of the drug, and in
used in the elderly, provided that renal insufficiencyturn may help to prevent gains in bodyweight. Col-and other exclusions are not present. A difficulty inlectively, the cellular effects of metformin serve to
practice is that significant renal dysfunction may becounter insulin resistance and to reduce the putativepresent without the aforementioned elevation of se-toxic metabolic effects of hyperglycaemia (glucoserum creatinine.toxicity) and fatty acids (lipotoxicity) in type 2
diabetes. The improvement in insulin sensitivity can cause
ovulation to resume in cases of anovulatory polycys-3.1.2 Pharmacokinetics
tic ovary syndrome (PCOS) [an unlicensed applica-Metformin is a stable hydrophilic biguanide that
tion of the drug in the absence of diabetes].[45]is quickly absorbed and eliminated unchanged in the
Metformin should be taken with meals or immed-urine. It is imperative that metformin is only pre-
iately before meals to minimise possible gastrointes-scribed to patients with renal function that is suffi-
tinal adverse effects. Treatment should be startedcient to avoid accumulation of the drug. Renal clear- with 500 or 850mg once daily, or 500mg twice dailyance of metformin is achieved more by tubular
(one tablet with the morning and evening meals).secretion than glomerular filtration, the only signif-The dosage is increased slowly one tablet at a timeicant drug interaction being competition with cime- at intervals of about 2 weeks until the target leveltidine, which can increase plasma metformin con-
of glycaemic control is attained. If the target is notcentrations. There is little binding of metformin to
plasma proteins. Metformin is not metabolised, and attained and an additional dose produces no greater
so does not interfere with the metabolism of co- effect, return to the previous dose and, in the case ofadministered drugs. Metformin is widely distribut- monotherapy, consider combination therapy by ad-ed, high concentrations being retained in the walls of ding in another agent (e.g. a sulphonylurea, prandialthe gastrointestinal tract; this provides a reservoir
insulin releaser or thiazolidinedione). The maximalfrom which plasma concentrations are maintained. effective dosage appears to be about 2000 mg/day,Nevertheless, peak plasma metformin concentra-
given in divided doses with meals, the absolutetions are short-lived: in patients with normal renal
maximum being 2550 or 3000 mg/day in differentfunction the plasma half-life (t1/2) for metformin is
countries. Several single tablet combinations of a25 hours, and almost 90% of an absorbed dosage is
sulphonylurea (usually glibenclamide) with a bigua-eliminated within 12 hours.[40]
nide (metformin or phenformin) have been available
in some European countries and elsewhere for more3.1.3 Indications and Contraindicationsthan a decade. A slow-release formulation of met-Metformin is the therapy of choice for over-formin and a fixed-dose combination of metforminweight and obese patients with type 2 diabetes.[42] It
with glibenclamide is available in the UScan be equally effective in normal weight patients.(Glucovance, Bristol-Myers Squibb Company,Metformin can also be used in combination with any
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402 Krentz & Bailey
Princeton, NJ, USA)1 and elsewhere (although not secretion. Indeed, the reduction of basal insulin con-
in the UK). A combined rosiglitazone/metformin centrations, notably in hyperinsulinaemic patients,
(Avandamet, GlaxoSmithKline, Philadelphia, PA, should itself improve insulin sensitivity by relieving
USA) [see section 3.2] preparation is also available the insulin-induced downregulation of insulin recep-
in some parts of the world. tor number and suppression of post-receptor insulin
pathways.[35] Bodyweight tends to stabilise or de-During long-term treatment with metformin it is
crease slightly during metformin therapy. Small im-advisable to check (e.g. annually) for the develop-
provements in the blood lipid profile may be observ-ment of contraindications, particularly an elevated
ed in hyperlipidaemic patients; plasma concentra-serum creatinine concentration (yearly measurement
tions of triglycerides, fatty acids and low-densityof creatinine clearance posing practical difficulties).
lipoprotein (LDL)-cholesterol tend to fall, whereasMetformin can reduce gastrointestinal absorption of
cardioprotective HDL-cholesterol tends to rise.cyanocobalamin (vitamin B12). While anaemia is
These effects appear to be independent of the anti-very rare, an annual haemoglobin measurement is
hyperglycaemic effect, although a lowering of trig-prudent in patients at risk of nutritional deficiencies.lyceride and free fatty acids is likely to help improveIt is advised to stop metformin treatment temporari-
insulin sensitivity and benefit the glucose-fatty acidly during use of intravenous radiographic contrast
cycle.media, surgery and any other intercurrent situation
in which the exclusion criteria could be invoked.[46] In the UKPDS, overweight patients who started
Substitution with insulin may be appropriate at such oral antidiabetic therapy with metformin showed a
times. Metformin alone is unlikely to cause serious statistically significant 39% reduced risk of myocar-
hypoglycaemia, but hypoglycaemia becomes an is- dial infarction compared with conventional treat-
sue when metformin is used in combination with an ment (p = 0.01).[47] No clear relationship is evident
insulin-releasing agent or insulin. between metformin dosage and decreased coronary
artery events. This suggests that patients who can3.1.4 Efficacy only tolerate a low dosage of metformin may benefit
The long-term blood glucose-lowering efficacy from continuing the drug, even when other agents
of metformin is broadly similar to sulphonylureas. have to be added to optimise glycaemic control. The
As monotherapy in patients who are not adequately decrease in myocardial infarction observed with
controlled on nonpharmacological therapy, optimal- metformin therapy in the UKPDS was not attributa-
ly titrated metformin therapy typically reduces fast- ble to more effective lowering of HbA1c or major
ing plasma glucose by 24 mmol/L, corresponding effects on classic cardiovascular risk factors such as
to a decrease in HbA1c by approximately 12%.[40] plasma lipids. Consequently, other potentially
The effect is dependent upon the presence of some vasoprotective effects of metformin have been in-
endogenous -cell function, and is largely indepen- voked. Reported benefits of metformin on non-clas-dent of bodyweight, age and duration of diabetes. sic cardiovascular risk factors (table V) include in-
However, given the progressive nature of type 2 creased fibrinolysis and a reduced concentration of
diabetes, re-assessment of dosage and consideration the anti-thrombolytic factor plasminogen activator
of additional therapy are required to maintain gly- inhibitor-1 (PAI-1).[41,46] The mechanism of the
caemic control in the long term.[4,21] Metformin has cardioprotective effects of metformin remains un-
several features that mark it out as a good choice for certain. Detracting somewhat from this generally
first-line monotherapy. The anti-hyperglycaemic ac- favourable view was evidence of an initially greater
tion of metformin means that it is unlikely to cause mortality when metformin was added to a sulphony-
severe hypoglycaemia. This may be explained in lurea in a UKPDS substudy,[47] but longer-term fol-
part because metformin does not stimulate insulin low-up has shown the benefits of metformin to be
1 The use of trade names is for product identification purposes only and does not imply endorsement.
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404 Krentz & Bailey
ed metformin has been challenged by some authori-
ties, but dialysis may nonetheless be helpful in op-
timising fluid and electrolyte balance during treat-
ment with high-dose intravenous bicarbonates.[54]
3.2 Thiazolidinediones
Thiazolidinediones improve whole-body insulin
Table VI. Metabolic effects of thiazolidinediones[55]
Adipose tissue Muscle Liver
Glucose uptake Glucose uptake Gluconeogenesis
Fatty acid uptake Glycolysis Glycogenolysis
Lipogenesis Glucose oxidation Lipogenesis
Pre-adipocyte Glycogenesisa Glucose uptakea
differentiation
a Inconsistent findings.
indicates increase; indicates decrease.sensitivity via multiple actions on gene regulation.
These effects result from stimulation of a nuclearglucose uptake via glucose transporter-4 in skeletalreceptor peroxisome proliferator-activated receptor-muscle, and some reports indicate that rates of glu-(PPAR), for which thiazolidinediones are potentconeogenesis in the liver are reduced. Stimulation ofsynthetic agonists.[55] The antidiabetic activity oflipogenesis via PPAR reduces circulating non-es-
thiazolidinediones was described in the early 1980s, terified fatty acid (NEFA) concentrations throughtroglitazone being the first of the class to becomecellular uptake and triglyceride synthesis (figure 5).available for clinical use. Troglitazone was intro-The reduction in plasma NEFA concentrations isduced in the US in 1997, only to be withdrawn inassociated with increased glucose utilisation and2000 because of cases of idiosyncratic hepato-reducing gluconeogenesis by reducing operation oftoxicity resulting in fatalities. Troglitazone wasthe glucose-fatty acid cycle; reductions in ectopicavailable in the UK for only for a few weeks in 1997lipid deposition in muscle and liver may contributebefore being withdrawn by its distributor as reportsto the improvements on glucose metabolism. Thia-of hepatotoxicity accumulated in other countries. Tozolidinediones also reduce the production and ac-date, two other thiazolidinediones, rosiglitazone andtivity of the adipocyte-derived cytokine tumour ne-pioglitazone, have not shown the hepatotoxicity that
crosis factor (TNF)-.[55] The latter has been impli-led to the demise of troglitazone. Rosiglitazone andcated in the development of impaired insulin actionpioglitazone were introduced in the US in 1999 andin muscle,[58] although the precise role of TNF inin Europe in 2000.[56] Combination preparationshuman states of insulin resistance remains unclear.(e.g. thiazolidinedione plus metformin) are alsoReductions in plasma insulin concentrations andavailable.lowering of circulating triglycerides are additional
3.2.1 Mode of Action indirect mechanisms that may help to improveStimulation of PPARis regarded as the principal whole-body insulin sensitivity. Thiazolidinediones,
mechanism through which thiazolidinediones en- like metformin, are anti-hyperglycaemic agents andhance insulin sensitivity. PPAR is expressed at require the presence of sufficient insulin to generatehighest levels in adipose tissue, and less so in
a significant blood glucose-lowering effect.muscle and liver. PPAR operates in association3.2.2 Pharmacokineticswith the retinoid X receptor. The resulting heter-
odimer binds to nuclear response elements, thereby Rosiglitazone and pioglitazone are rapidly, and
modulating transcription of a range of insulin-sensi- nearly completely absorbed (12 hours to peak con-
tive genes, in the presence of necessary cofactors centration), although absorption is slightly delayed
(figure 4).[55,57] Many of the genes activated or sup- when taken with food. Both agents are extensively
pressed by thiazolidinediones are involved in lipid metabolised by the liver. Rosiglitazone is metabol-
and carbohydrate metabolism (table VI). Stimula- ised mainly to very weakly active metabolites with
tion of PPAR by a thiazolidinedione promotes lesser activity that are excreted predominantly in thedifferentiation of pre-adipocytes with accompany- urine. The metabolites of pioglitazone are more
ing lipogenesis, effects that promote or enhance the active and excreted mainly in the bile. Metabolismlocal effects of insulin. Thiazolidinediones increase of rosiglitazone is undertaken mainly by cyto-
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Oral Antidiabetic Agents 405
chrome P450 (CYP) 2C8, which is not a widely thiazolidinediones.[60] Substituting a thiazolidine-
activated isoform of CYP.[59] Thus, rosiglitazone dione for either a sulphonylurea or metformin in
does not interfere with the metabolism of otherpatients with inadequate glycaemic control is gener-drugs. Pioglitazone is metabolised in part by ally of limited value and risks a temporary deteriora-
CYP3A4 but, to date, no clinically significant reduc- tion in glycaemic control because of the slow onsettions in plasma concentrations of other drugs (e.g. of action of thiazolidinediones. Having been disap-oral contraceptives) has been reported. Although pointed with this experience, some UK diabetolo-both thiazolidinediones are almost completely gists have elected to use thiazolidinediones in com-bound to plasma proteins, their concentrations are bination with both a sulphonylurea and metfor-low and have not been reported to interfere with min.[60] The former strategy has met with variableother protein-bound drugs. success: some patients respond well, others show
little response, requiring transfer to insulin. The3.2.3 Indications and Contraindications
combination of thiazolidinedione plus insulin canIn the US, rosiglitazone and pioglitazone are improve glycaemic control while reducing insulin
available for use as monotherapy in non-obese anddosages in obese patients, although peripheral oede-
obese patients with type 2 diabetes in whom diabe-ma has been reported.[61]
tes is not adequately controlled by nonpharmacolo-The main cautions to using thiazolidinediones aregical measures. They can also be used in combina-
listed in table VII. Rosiglitazone and pioglitazonetion with various other antidiabetic drugs and incan cause fluid retention with increased plasma vol-combination with insulin. In Europe, rosiglitazoneume, a reduced haematocrit and a decrease inand pioglitazone can be used as monotherapy if thehaemoglobin concentration. Therefore, the risk ofpatient is contraindicated for or intolerant of metfor-
oedema and anaemia should be taken into account,min. Thiazolidinediones can be used in combination
and in Europe, use of thiazolidinediones in patientswith metformin or a sulphonylurea. In Europe, com-bination with insulin remains a contraindication to with any evidence of congestive heart disease or
Thiazolidinedione Glucose Fatty acids
GLUT-4
Glucose uptake
and utilisation
aP2, acyl-
CoA synthase
Lipogenesis
and adipocyte
differentiation
Lipoprotein
lipase
Transcription of cer tain
insulin-sensitive genes
PPAR RXR
Adipocyte
Hydrolysis ofcirculating triglycerides
in chylomicrons and VLDL
FATP
Fig. 5. Mechanism of action of a thiazolidinedione on an adipocyte (reproduced from Krentz and Bailey, [4] with permission from the Royal
Society of Medicine Press). aP2 = adipocyte fatty acid binding protein; CoA = coenzyme A; FATP = fatty acid transporter protein; GLUT-4 =
glucose transporter-4; PPAR= peroxisome proliferator-activated receptor-; RXR = retinoid X receptor; VLDL = very low-density lipopro-teins; indicates increase.
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406 Krentz & Bailey
is some evidence for a modest blood pressure-lower-
ing effect.[63]
As a precautionary measure, liver functionshould be assessed by measuring serum ALT before
starting therapy and subsequently at 2-monthly in-
tervals (or, in the US, as judged necessary by the
prescribing clinician) during the first year of treat-
ment; thereafter, periodic monitoring of liver func-
tion is prudent. Pre-existing liver disease, the devel-
opment of clinical hepatic dysfunction or elevated
ALT levels >2.5 times the upper limit for the labora-
tory serve as contraindications to thiazolidinedi-
ones. However, as mentioned earlier, hepatotoxicityhas not been a concern with either rosiglitazone or
pioglitazone. Isolated cases of nonfatal hepatocellu-
lar damage have been reported; however, the issue is
clouded by reports suggesting an intrinsically higher
risk of liver failure in patients with type 2 diabetes.
Nevertheless, precautionary monitoring of liver
function remains advisable. When initiating therapy
with rosiglitazone or pioglitazone, blood glucose
monitoring and titration of drug dosage should be
undertaken while bearing in mind that thiazolidine-
diones exert a slowly generated anti-hypergly-
Table VII. Cautions in the use of thiazolidinediones
Active liver disease
This remains a contraindication to the use of thiazolidinediones
even though neither rosiglitazone nor pioglitazone have beenassociated with troglitazone-like hepatotoxicity. In fact, the latter
drugs are under investigation as a potential treatment for non-
alcoholic steatohepatitis. In 2004, the US FDA recommendation
for 2-monthly monitoring of biochemical liver function tests was
relaxed. Instead, periodic biochemical monitoring is now left to
the supervising clinicians discretion
Heart failure
The precise contraindications differ between countries. In Europe,
current heart failure or a history of heart failure are
contraindications to thiazolidinediones
Insulin treatment
Although rosiglitazone and pioglitazone are licensed in the US for
use in combination with insulin, caution is required. Concernsabout higher rates of heart failure underlie this concern. The
European Agency for the Evaluation of Medicinal Products
considers insulin therapy a contraindication to the use of
thiazolidinediones
Pregnancy and breast-feeding
Thiazolidinediones are classified as pregnancy category C
because of growth retardation in mid-to-late gestation in animal
models. These drugs should only be used during pregnancy if the
potential benefit justifies the potential risk to the fetus
Polycystic ovary syndrome
Thiazolidinediones can cause ovulation to recommence in women
with hyperandrogenism and chronic anovulation; risk of
pregnancy
caemic effect that usually requires 23 months to
reach maximum effect.heart failure is contraindicated. The choice of which
patients to exclude on the basis of cardiac status According to the EU license, rosiglitazone can bevaries between the product labelling sheets in the given at a dosage of 4 mg/day in combination with aUS and Europe. Consensus guidelines from the sulphonylurea, increasing to 8 mg/day (either onceAmerican Heart Association and the American Dia- daily or in divided doses) in combination with met-betes Association have recently been published.[62] formin. Pioglitazone can be given as a once-dailyPatients treated with a combination of insulin plus dosage of 15mg, increasing to 30mg if necessarythiazolidinedione appear to be at highest risk of (maximum 45mg in the US and Europe). The thera-oedema, although the absolute rate of cardiac failure peutic response varies markedly between patientsis low despite the fact the diabetes is a major risk and it can be difficult to predict those most likely tofactor for this complication.[62] The guidelines urge a respond. If no effect is observed after 3 months it iscautious approach and careful clinical monitoring, appropriate to consider the patient as a nonresponderespecially for patients likely to be at higher risk of and to stop the treatment. Rosiglitazone and piog-cardiac failure. The haemogloblin concentration litazone can be used in the elderly, provided thereshould be checked before starting a thiazolidine- are no contraindications. Both drugs may be used indione, bearing in mind that reductions of up to 1 g/ patients with mild-to-moderate renal impairment,
dL in haemoglobin concentration may occur during although the potential for oedema is a concern. In
therapy. No adverse effects on blood pressure have women with anovulatory PCOS the improvement in
been noted with the thiazolidinediones, even with insulin sensitivity may cause ovulation to resumeduring thiazolidinedione therapy. A combinationthe increase in plasma volume; on the contrary, there
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Oral Antidiabetic Agents 407
preparation containing rosiglitazone plus metformin subcutaneous depots increase as new small, insulin-
(Avandamet; combining rosiglitazone/metformin sensitive adipocytes are formed. There are provi-
in strengths 1mg/500mg, 2mg/500mg, 4mg/500mg, sional data to suggest that thiazolidinediones exert a
2mg/1000mg, although not all strengths are avail- range of effects on aspects of the metabolic syn-
able in all countries). drome that might reduce the risk of atherosclerotic
cardiovascular disease.[63,65] For example, thiazoli-3.2.4 Efficacy dinediones have been reported to downregulate
Addition of rosiglitazone or pioglitazone to the PAI-1 expression. Thiazolidinediones have also
treatment schedule of patients whose glycaemic been reported to decrease urinary albumin excretion
control with a sulphonylurea or metformin is subop- to a greater extent than expected for the improve-
timal has consistently resulted in significant reduc- ment in glycaemic control and to reduce circulating
tions in HbA1c. As judged by the available literature, markers of chronic low-grade inflammation.
these agents have similar glucose-lowering effects, Preclinical studies suggesting that treatment of glu-
reducing HbA1c by around 0.51.5%.[64] However, cose-intolerant animals with a thiazolidinedionethe participants in these clinical trials had known preserved -cell function have yet to be confirmeddiabetes of several years duration, the effects of in human studies. In insulin-resistant women with a
thiazolidinediones being more apparent when -cell history of gestational diabetes at high risk of type 2function is less impaired. While earlier use of thia- diabetes troglitazone reduced the incidence of new-
zolidinediones may be advantageous, the longer- onset diabetes.[66] Whether thiazolidinediones will
term picture requires clarification. Estimates of in- prove more effective than conventional antidiabetic
sulin sensitivity and -cell function (based on ana- agents in reducing the decline in -cell function inlysis of fasting glucose and insulin concentrations) patients with established type 2 diabetes remains to
have indicated that both defects can be improved by be determined, although preliminary data in patients
the addition of a thiazolidinedione.[64]
The effects on who respond to the drugs have been encouraging.[67]
plasma lipids and apoproteins have been the subject Also of considerable interest are the clinical impli-
of debate. Rosiglitazone can cause a small rise in the cations of the aforementioned effects of thiazolidi-
total cholesterol concentration, which stabilises nediones on risk factors for cardiovascular disease.
within about 3 months. This is accounted for by a These effects, allied to direct anti-atherogenic ac-
rise in both the LDL-cholesterol and the HDL-cho- tions reported in animal studies, are presently being
lesterol, leaving the LDL : HDL-cholesterol ratio studied in clinical trials with cardiovascular end-
and the total : HDL-cholesterol ratio little changed points.[68]
or slightly raised. Pioglitazone generally appears to
have little effect on total cholesterol, and has been 3.2.5 Adverse Effects
shown to reduce triglyceride concentrations in sev- Rosiglitazone and pioglitazone are generally well
eral studies. Both thiazolidinediones reduce the pro- tolerated. As noted in section 3.2.3, caution is ad-
portion of the smaller, more dense (more atherogen- vised in heart disease; in the UK this includes a
ic) LDL particles.[64] To date, no prospective com- history of cardiac failure, oedema, anaemia and liver
parative studies of the two drugs have been reported function requiring intermittent monitoring in accor-
and the clinical implications of these changes are dance with the package labelling. If contraindica-
uncertain.[63] tions arise during treatment, monitoring should be
Weight gain, similar in magnitude to sulphonylu- intensified and, if necessary, treatment discontin-
rea therapy (typically 14kg) and stabilising over ued. Hypoglycaemia may occur several weeks after
612 months, has been observed during thiazo- adding a thiazolidinedione to a sulphonylurea; self-
lidinedione therapy. There is some evidence that the monitoring of blood glucose can be helpful in identi-
distribution of body fat is altered such that visceral fying the point at which the dosage of the sulphony-adipose depots are little changed or reduced, while lurea should be reduced. Since PPARis expressed
2005 Adis Data Information BV. All rights reserved. D